Many clinical diseases are associated with abnormal responses to foreign and self antigens. The proper regulation of immune reactions is usually mediated by lymphocytes which are regulatory or suppressor in function. Examples of abnormal suppressor cell function are seen in classic immunodeficiency diseases, neoplasms, chronic infections, and autoimmune diseases such as systemic lupus erythematosus (SLE). Thus, abnormalities in suppressor cell function appear to directly contribute to the pathogenesis of a wide variety of diseases involving autoimmunity and lymphoproliferation. NZB x NZW F1 mice spontaneously develop manifestations of autoimmunity which are similar in many respects to patients with SLF. We have developed a model of selective suppressor cell loss in these mice which results in a marked acceleration of their SLE-like disease. The proposed study will be to extend these findings and develop a model of selective suppressor cell defect in a "normal" mouse strain not predisposed to the development of autoimmune disease. The model will be developed by using daily administration of a naturally occurring thymocytotoxic antibody (NTA) which selectively accelerates suppressor cell dysfunction in NZB/NZW mice. NTA is an autoantibody which is similar in many respects to antilymphocyte autoantibodies found in SLE patients. NTA will be given from infancy to normal mice which are either intact, thymectomized, or moderately altered immunologically by the use of irradiation and/or anti-lympocyte serum. Suppressor cell function will be assayed by: 1) the ability to produce suppressor cells in vitro after exposure to Con-A and 2) the ability of cells from treated mice to regulate graft-vs-host responses. The selectivity of the suppressor cell loss will be studied by determining whether generalized effector cell function is intact; i.e., documenting the response to mitogens, allogeneic antigens, immunizations, and allograft rejection. Non-autoimmune animals with a selective suppressor cell defect will enable study of the pathogenesis of autoimmune disease.